The overall objective of this renewal application is to sustain and expand the PI's patient-oriented research program in the pharmacology of opioids and HIV/AIDS drugs, specifically directed towards the therapy of substance abuse and pain. A principal component of this program will be the development of beginning clinical investigators. The specific research objectives are to 1) continue existing research which investigates mechanisms of variability in human opioid disposition, pharmacodynamics and clinical efficacy, and endeavors to optimize opioid therapy of substance abuse and cancer pain, 2) expand existing research on the mechanism of drug interactions with HIV/AIDS drugs and their clinical consequence, 3) facilitate program expansion into underutilized therapies such as nonsteroidal antiinflammatory drugs, and 4) mentor beginning clinical investigators in patient-oriented research, utilizing the above framework to spawn independent research programs. A critical focus will be interfacing in vitro and in vivo aspects of human drug disposition and efficacy, and translating recent discoveries in basic enzymology and pharmacogenetics of drug disposition into clinical strategies for optimized therapy. Methadone maintenance is the cornerstone of opiate abuse therapy, a vital and effective strategy for HTV/AIDS risk reduction, and widely used for cancer pain treatment. Methadone is characterized by extreme, unexplained, and unpredictable interindividual pharmacokinetic variability, causing inadequate pain treatment, opioid abstinence syndrome, treatment failures, and unwanted side effects. Methadone is metabolized by hepatic and intestinal cytochrome P450, and is a substrate for transporters in the intestine, brain, and kidney. Mechanism(s) of individual variability in methadone metabolism and transport are, however, unknown, as are their clinical consequences. Highly active antiretroviral therapy (HAART) is the cornerstone HIV/AIDS treatment, yet HIV/AIDS drugs cause profound, complex, and poorly understood drug interactions. To address these questions, experiments in vitro will use human liver and intestinal microsomes and transfected cell lines to identify relevant P450 isoforms and transporters and probe drug-drug interactions. Complementary clinical investigations will verify these identifications and establish the mechanism of HTV/AIDS drug interactions, and the influence of drug interactions and pharmacogenetics on opioid disposition and pharmacologic effects. Successful identification of the factors affecting metabolism, clearance, and clinical effects of methadone will improve the clinical outcome and reduce the costs of opiate addiction and cancer pain treatment. Successful identification of the mechanism of HIV/AIDS drug interactions will improve the therapy of HIV/AIDS.